A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data

Hu, Hao; Roach, Jared C.; Coon, Hilary; Guthery, Stephen L.; Voelkerding, Karl V.; Margraf, Rebecca L.; Durtschi, Jacob D.; Tavtigian, Sean V.; Shankaracharya, _; Wu, Wilfred; Scheet, Paul; Wang, Shuoguo; Xing, Jinchuan; Glusman, Gustavo; Hubley, Robert; Li, Hong; Garg, Vidu; Moore, Barry; Hood, Leroy; Galas, David J.; Srivastava, Deepak; Reese, Martin G.; Jorde, Lynn B.; Yandell, Mark; Huff, Chad

doi:10.1038/nbt.2895

Cited by 95 publications

(90 citation statements)

References 45 publications

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“…pVAAST incorporates linkage, association, and variant severity. This method has been shown to be superior to other methods in analyzing genome sequencing data for autosomal dominant, autosomal recessive, and particularly relevant to the MRKH phenotype, dominant inheritance resulting from de novo mutations (40). Digenic/polygenic disease is also amenable to pVAAST analysis (40).…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families

Williams

Ekşi

Shen

et al. 2017

Fertility and Sterility

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Objective To study the genetic cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Although a few candidate genes and genomic domains for have been reported for MRKH, the genetic underpinnings remain largely unknown. Some of the top candidate genes are WNT4, HNF1B, and LHX1. The goals of this study were to: 1) determine the prevalence of WNT4, HNF1B, and LHX1 point mutations, as well as new copy number variants (CNVs) in people with MRKH; and 2) identify and characterize MRKH cohorts. Design Laboratory and community based study Setting Academic medical centers Patients 147 MRKH probands and available family members Interventions DNA sequencing of WNT4, HNF1B, and LHX1 in 100 MRKH patients; chromosomal microarray analysis in 31 North American MRKH patients; and ascertainment and sample collection of 147 North American and Turkish MRKH probands and their families Main Outcome Measure(s) DNA sequence variants and CNVs; pedigree structural analysis Results We report finding CNVs in 6/31 (~19%) people with MRKH, but no point mutations or small indels in WNT4, HNF1B, or LHX1 in 100 MRKH patients. Our MRKH families included 43 quads, 26 trios, and 30 duos. Of our MRKH probands, 87/147 (59%) had MRKH type 1 and 60/147 (41%) had type 2 with additional anomalies. Conclusions Although the prevalence of WNT4, HNF1B, and LHX1 point mutations is low in people with MRKH, the prevalence of CNVs was about 19%. Further analysis of our large familial cohort of patients will facilitate gene discovery to better understand the complex etiology of MRKH.

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Section: Discussionmentioning

confidence: 99%

Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families

Williams

Ekşi

Shen

et al. 2017

Fertility and Sterility

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“…Sequence alignment to the human reference genome (UCSC hg19) was performed using the Burrows-Wheeler Aligner algorithm, 40 and variant calling was performed using the Genome Analysis Toolkit (Broad Institute, Cambridge, MA, USA). 41 The following criteria were used to generate a list of variants for each family for follow-up genotyping of other family members and cosegregation analysis: (1) on the assumption that disease-causing variants were rare, we excluded all common single-nucleotide polymorphisms (MAF41%) in dbSNP v.137; (2) the variant was shared between individuals with ET within a family; and (3) the variant was ranked by the software tool pVAAST (see Web Resources) 42 (using a dominant model and the maximum number of permutations of 1 000 000) with P-value o0.05.…”

Section: Whole-exome Sequencing Analysismentioning

confidence: 99%

Identification of candidate genes for familial early-onset essential tremor

et al. 2015

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Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts L-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G4A (p. (Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C4T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved aminoacid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone.

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“…Such tools include linkage, 1 family-based association, 2 pedigree-aware imputation, pedigree-aware phasing, Mendelian error checking, heritability, and pVAAST (Pedigree Variant Annotation, Analysis, and Search Tool). 3 In many instances, knowing the pedigree that is consistent with the generated genetic data is crucial to solving the disease. [4][5][6][7] Additionally, the collection of samples from a limited geographical region for a genetic analysis might introduce biases toward unintentionally obtaining samples of unknown relatedness for which a previously unknown pedigree could be reconstructed and used.…”

Section: Introductionmentioning

confidence: 99%

PRIMUS: Rapid Reconstruction of Pedigrees from Genome-wide Estimates of Identity by Descent

Staples

Qiao

Cho

et al. 2014

The American Journal of Human Genetics

150

162

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Understanding and correctly utilizing relatedness among samples is essential for genetic analysis; however, managing sample records and pedigrees can often be error prone and incomplete. Data sets ascertained by random sampling often harbor cryptic relatedness that can be leveraged in genetic analyses for maximizing power. We have developed a method that uses genome-wide estimates of pairwise identity by descent to identify families and quickly reconstruct and score all possible pedigrees that fit the genetic data by using up to third-degree relatives, and we have included it in the software package PRIMUS (Pedigree Reconstruction and Identification of the Maximally Unrelated Set). Here, we validate its performance on simulated, clinical, and HapMap pedigrees. Among these samples, we demonstrate that PRIMUS can verify reported pedigree structures and identify cryptic relationships. Finally, we show that PRIMUS reconstructed pedigrees, all of which were previously unknown, for 203 families from a cohort collected in Starr County, TX (1,890 samples).

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A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data

Cited by 95 publications

References 45 publications

Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families

Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families

Identification of candidate genes for familial early-onset essential tremor

PRIMUS: Rapid Reconstruction of Pedigrees from Genome-wide Estimates of Identity by Descent

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